The Study of Fear Extinction: Implications for Anxiety Disorders

Graham, Bronwyn M.; Milad, Mohammed R.

doi:10.1176/appi.ajp.2011.11040557

Cited by 342 publications

(268 citation statements)

References 94 publications

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“…with avoidance, trait anxiety, and risk for anxiety disorders (Graham and Milad, 2011). Because adaptive fear responses are so central to survival, and reproductive success their neural substrates are highly conserved from rodent to human (LeDoux, 2012).…”

Section: Discussionmentioning

confidence: 99%

“…Mice lacking SERT display elevated anxiety-like behaviors and impaired fear extinction retention (Wellman et al, 2007). Decreased expression of SERT has been reported in individuals with anxiety disorders (Kang et al, 2010), which may contribute to impaired fear extinction learning reported in these disorders (Graham and Milad, 2011). Similarly, alterations in the serotonergic circuitry is seen in individuals with AN, a disorder characterized by CR (Kaye et al, , 2009).…”

Section: Discussionmentioning

confidence: 99%

“…Fear extinction occurs when, after fear conditioning, the CS alone is presented repeatedly and fear responses to the CS decrease. The ability to reassess cues of danger as safe has been associated with lower subjective experiences of anxiety, and inefficient fear extinction learning is present in a number of anxiety disorders (Graham and Milad, 2011). Because fear extinction learning is an active learning process that requires neural plasticity (Kaplan and Moore, 2011;Sotres-Bayon et al, 2007), genetic and pharmacologic factors that increase neural plasticity, can enhance fear extinction learning (Mao et al, 2006;Soliman et al, 2010;Sotres-Bayon et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

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Caloric Restriction Enhances Fear Extinction Learning in Mice

Riddle

McKenna

Yoon

et al. 2013

Neuropsychopharmacol

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Fear extinction learning, the ability to reassess a learned cue of danger as safe when it no longer predicts aversive events, is often dysregulated in anxiety disorders. Selective serotonin reuptake inhibitors (SSRI's) enhance neural plasticity and their ability to enhance fear extinction learning may explain their anxiolytic properties. Caloric restriction (CR) has SSRI-like effects on neural plasticity and anxiety-related behavior. We implemented CR in mice to determine its effects on conditioned-fear responses. Wild type and serotonin transporter (SERT) knockout mice underwent CR for 7 days leading to significant weight loss. Mice were then tested for cued fear learning and anxiety-related behavior. CR markedly enhanced fear extinction learning and its retention in adolescent female mice, and adults of both sexes. These effects of CR were absent in SERT knockout mice. Moreover, CR phenocopied behavioral and molecular effects of chronic fluoxetine, but there was no additive effect of CR in fluoxetine-treated mice. These results demonstrate that CR enhances fear extinction learning through a SERT-dependent mechanism. These results may have implications for eating disorders such as anorexia nervosa (AN), in which there is a high prevalence of anxiety before the onset of dietary restriction and support proposals that in AN, CR is a motivated effort to control dysregulated fear responses and elevated anxiety.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Caloric Restriction Enhances Fear Extinction Learning in Mice

Riddle

McKenna

Yoon

et al. 2013

Neuropsychopharmacol

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“…Individual variation in the integrity of this amygdala-prefrontal circuitry has been linked to trait anxiety and posttraumatic stress disorder, suggesting that exposure-based techniques may be least effective in those who suffer from anxiety disorders (3)(4)(5)(6)(7)(8)(9).…”

mentioning

confidence: 99%

Extinction during reconsolidation of threat memory diminishes prefrontal cortex involvement

Schiller

Kanen²,

LeDoux

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

260

254

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Controlling learned defensive responses through extinction does not alter the threat memory itself, but rather regulates its expression via inhibitory influence of the prefrontal cortex (PFC) over amygdala. Individual differences in amygdala-PFC circuitry function have been linked to trait anxiety and posttraumatic stress disorder. This finding suggests that exposure-based techniques may actually be least effective in those who suffer from anxiety disorders. A theoretical advantage of techniques influencing reconsolidation of threat memories is that the threat representation is altered, potentially diminishing reliance on this PFC circuitry, resulting in a more persistent reduction of defensive reactions. We hypothesized that timing extinction to coincide with threat memory reconsolidation would prevent the return of defensive reactions and diminish PFC involvement. Two conditioned stimuli (CS) were paired with shock and the third was not. A day later, one stimulus (reminded CS+) but not the other (nonreminded CS+) was presented 10 min before extinction to reactivate the threat memory, followed by extinction training for all CSs. The recovery of the threat memory was tested 24 h later. Extinction of the nonreminded CS+ (i.e., standard extinction) engaged the PFC, as previously shown, but extinction of the reminded CS+ (i.e., extinction during reconsolidation) did not. Moreover, only the nonreminded CS+ memory recovered on day 3. These results suggest that extinction during reconsolidation prevents the return of defensive reactions and diminishes PFC involvement. Reducing the necessity of the PFC-amygdala circuitry to control defensive reactions may help overcome a primary obstacle in the long-term efficacy of current treatments for anxiety disorders.fear | Pavlovian conditioning | defense | learning E fforts to control maladaptive defensive reactions through extinction or exposure therapy are sometimes short-lived because these techniques do not significantly alter the threat memory itself, but rather regulate its expression via the prefrontal cortex's (PFC) inhibition of the amygdala (1, 2). Individual variation in the integrity of this amygdala-prefrontal circuitry has been linked to trait anxiety and posttraumatic stress disorder, suggesting that exposure-based techniques may be least effective in those who suffer from anxiety disorders (3-9).Recently, it has been shown in mice (10, 11), rats (12), and humans (13-16) that precisely timing behavioral extinction to coincide with memory reconsolidation can persistently inhibit the return of defensive reactions (but see refs. 17-19 for a discussion of boundary conditions). Reconsolidation is the state to which memories enter upon retrieval, which makes them prone to interference (20)(21)(22). Behavioral interference of reconsolidation using extinction has been linked to alterations in glutamate receptor function in the amygdala, which plays a critical role in memory plasticity (10,12). These findings are consistent with the suggestion that, in contrast to standar...

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“…Like social anxiety disorder, a commonly replicated finding from various PTSD populations is hyperactivity of the amygdala in response to masked fearful faces or trauma-related stimuli [3,28,29]. This manifests as higher amygdala reactivity as compared to non-PTSD groups and/or a positive correlation between severity of PTSD symptoms and amygdala reactivity [28,[30][31][32][33].…”

Section: Amygdala Reactivity In Anxiety Disordersmentioning

confidence: 99%